The long-term goal of this proposal is to uncover the mechanisms of disabling painful neuropathic disease, such as causalgia. Although exact mechanisms are not clear, two types of neuropathic pain can be distinguished based on sympathetic dependency: sympathetically maintained pain (SMP) and sympathetically independent pain (SIP). In recent years, several animal models have been developed to investigate the mechanisms of neuropathic pain. Some of these models seem to represent SMP while others represent SIP. The present proposal uses these models to investigate the role of the sympathetic nervous system in neuropathic pain. Three specific aims are proposed. The first aim tests the hypothesis that proximal injury of a peripheral nerve induces SMP and distal injury induces SIP. This will be tested in 3 neuropathic pain models with injuries at different locations, using behavioral testing, immunohistochemical and electrophysiological methods. Second, to test the hypothesis that both SMP and SIP are maintained by a common mechanism of spinal sensitization caused by input of ectopic discharges arising from injured sensory neurons, correlations between ectopic discharges of injured afferent neurons and neuropathic pain behaviors in the 3 models will be made first and then the effects of blocking the spinal input from ectopic discharges on pain behaviors will be examined. Third, to test the hypothesis that certain pain states which are not influenced by denervation of sympathetic nerves (SIP) may still depend on adrenergic receptors, adrenergic dependency will be tested in the 3 models using behavioral tests and electrophysiological methods. Successful completion of this proposal is expected to accomplish 3 goals: 1) to determine which type of injuries produce sympathetically dependent neuropathic pain; 2) to establish limitations of various animal models for neuropathic pain (which is helpful in choosing a model for experimental studies); and 3) to introduce the concept of "adrenergically maintained pain." Furthermore, the present proposal will have an important clinical implication in that it may lead to an improved diagnostic classification of neuropathic pain patients which in turn will help determine treatment strategies.